Archiv der Pharmazie

Ursolic acid: Pharmacokinetics process in vitro and in vivo, a mini review
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Ursolic acid (UA) is a natural triterpene compound found in various fruits and vegetables, with antitumor, anti‐inflammatory, anti‐oxidant, anti‐apoptotic, anti‐allergy, and anti‐carcinogenic
effects. This review summarizes the pharmacokinetic features of free UA and some novel UA preparations in vitro and in vivo, thus providing a reference for rational utilization and drug design of UA.
Abstract Ursolic acid (UA) is a natural triterpene compound found in various fruits and vegetables. UA has a widespread pharmacologic effect, including antitumor, anti‐inflammatory, anti‐oxidant,
anti‐apoptotic, anti‐allergy, and anti‐carcinogenic effects. UA can be used as an alternative medicine for the treatment and prevention of many diseases. However, the bioavailability of UA by oral
administration is low since it is absorbed by the intestine through passive diffusion. Therefore, some novel technologies are used to produce UA preparations that can change the pharmacokinetics
process and increase its solubility and bioavailability. At present, pharmacokinetic studies on UA are few. In this paper, we will review the pharmacokinetics features of free UA and some novel UA
preparations in vitro and in vivo, in order to provide a reference for rational utilization and drug design of UA.
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Potent and highly selective dual‐targeting monoamine oxidase‐B inhibitors: Fluorinated chalcones of morpholine versus imidazole
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Two series of fluorinated chalcones containing morpholine and imidazole‐based compounds (f1–f8) were synthesized and evaluated for MAO‐A and MAO‐B as well as AChE inhibitory activities.
Morpholine‐containing chalcones were highly selective MAO‐B inhibitors and all imidazole‐based fluorinated chalcones showed weak MAO inhibition in both isoforms. All morpholine‐containing compounds
also exhibited good blood–brain barrier permeation. Abstract Two series of fluorinated chalcones containing morpholine and imidazole‐based compounds (f1–f8) were synthesized and evaluated for
recombinant human monoamine oxidase (MAO)‐A and ‐B as well as acetylcholinesterase inhibitory activities. Our results indicate that morpholine containing chalcones are highly selective MAO‐B
inhibitors having reversibility properties. All the imidazole‐based fluorinated chalcones showed weak MAO inhibitions in both isoforms. Among the tested compounds,
(2E)‐3‐(3‐fluorophenyl)‐1‐[4‐(morpholin‐4‐yl)phenyl]prop‐2‐en‐1‐one (f2) showed potent inhibitory activity for recombinant human MAO‐B (IC50 = 0.087 μM) with a high selectivity index (SI) of 517.2.
In the recovery experiments using dialysis, the residual activity of MAO‐B inhibited by f2 was close to that with the reversible reference inhibitor. Inhibition assays revealed that the Ki values of
f1 and f2 for MAO‐B were 0.027 and 0.020 μM, respectively, with competitive patterns. All the morpholine‐based compounds (f1–f4) showed moderate inhibition toward acetylcholinesterase with IC50
values ranging between 24 and 54 μM. All morpholine‐containing compounds exhibit good blood–brain barrier permeation in the PAMPA method. The rational approach regarding the highly selective MAO‐B
inhibitor f2 was further ascertained by induced fit docking and molecular dynamics simulation studies.
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Synthesis and biological evaluation of sphingosine kinase 2 inhibitors with anti‐inflammatory activity
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Inhibitors of sphingosine kinase 2 (SphK2) with novel structural scaffolds were obtained, of which 7‐bromo‐2‐(2‐phenylethyl)‐2,3,4,5‐tetrahydro‐1,4‐epoxynaphtho[1,2‐b]azepine, a selective inhibitor
of SphK2, is particularly interesting as it does not exert any cytotoxic effects and has a potent anti‐inflammatory effect. It was found to inhibit mononuclear cell adhesion to a dysfunctional
endothelium. Abstract The synthesis of inhibitors of SphK2 with novel structural scaffolds is reported. These compounds were designed from a molecular modeling study, in which the molecular
interactions stabilizing the different complexes were taken into account. Particularly interesting is that 7‐bromo‐2‐(2‐phenylethyl)‐2,3,4,5‐tetrahydro‐1,4‐epoxynaphtho[1,2‐b]azepine, which is a
selective inhibitor of SphK2, does not exert any cytotoxic effects and has a potent anti‐inflammatory effect. It was found to inhibit mononuclear cell adhesion to the dysfunctional endothelium with
minimal impact on neutrophil–endothelial cell interactions. The information obtained from our theoretical and experimental study can be useful in the search for inhibitors of SphK2 that play a
prominent role in different diseases, especially in inflammatory and cardiovascular disorders.
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Synthesis, CYP 450 evaluation, and docking simulation of novel 4‐aminopyridine and coumarin derivatives
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A series of novel compounds based on the structure of 4‐aminopyridine, glatiramer acetate, and coumarin via C–N bond formation were synthesized and their toxicities, K+ channel blocker affinities and
PAD4 inhibitory activities were investigated compared to 4‐aminopyridine as a known CNS drug. All compounds, except for 4‐hydrazide pyridine, seem to be less toxic than 4‐aminopyridine. Abstract Four
series of novel compounds based on 4‐aminopyridine, glatiramer acetate, pyrone, and coumarin backbones were sufficiently synthesized and identified by spectroscopic methods. CYP enzyme inhibition
assays of five predominate human P450 isozymes indicate that all compounds, except for 4‐hydrazide pyridine 1c, seem to be less toxic than 4‐aminopyridine. Further investigation of the compounds
using molecular docking experiments revealed different, the same, or stronger binding modes for most of the synthesized compounds, with both polar and hydrophobic interactions with the 1WDA and 1J95
receptors compared to benzoyl l‐arginine amide and 4‐aminopyridine, respectively. These results introduce the synthesized compounds as K+ channel blockers that could be considered for in vivo CNS
disease studies.
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Bi‐heterocyclic benzamides as alkaline phosphatase inhibitors: Mechanistic comprehensions through kinetics and computational approaches
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Novel bi‐heterocyclic benzamides 8a–k were synthesized and assayed for their inhibitory effects on alkaline phosphatase. All these molecules were identified as potent inhibitors relative to the
standard used. Compound 8b inhibits alkaline phosphatase non‐competitively forming an enzyme–inhibitor complex. The computational study revealed these ligands to exhibit good binding energy values.
Abstract Novel bi‐heterocyclic benzamides were synthesized by sequentially converting 4‐(1H‐indol‐3‐yl)butanoic acid (1) into ethyl 4‐(1H‐indol‐3‐yl)butanoate (2), 4‐(1H‐indol‐3‐yl)butanohydrazide
(3), and a nucleophilic 5‐[3‐(1H‐indol‐3‐yl)propyl]‐1,3,4‐oxadiazole‐2‐thiol (4). In a parallel series of reactions, various electrophiles were synthesized by reacting substituted anilines (5a–k)
with 4‐(chloromethyl)benzoylchloride (6) to afford 4‐(chloromethyl)‐N‐(substituted‐phenyl)benzamides (7a–k). Finally, the nucleophilic substitution reaction of 4 was carried out with newly
synthesized electrophiles, 7a–k, to acquire the targeted bi‐heterocyclic benzamides, 8a–k. The structural confirmation of all the synthesized compounds was done by IR, 1H NMR, 13C NMR, EI‐MS, and CHN
analysis data. The inhibitory effects of these bi‐heterocyclic benzamides (8a–k) were evaluated against alkaline phosphatase, and all these molecules were identified as potent inhibitors relative to
the standard used. The kinetics mechanism was ascribed by evaluating the Lineweaver–Burk plots, which revealed that compound 8b inhibited alkaline phosphatase non‐competitively to form an
enzyme–inhibitor complex. The inhibition constant Ki calculated from Dixon plots for this compound was 1.15 μM. The computational study was in full agreement with the experimental records and these
ligands exhibited good binding energy values. These molecules also exhibited mild cytotoxicity toward red blood cell membranes when analyzed through hemolysis. So, these molecules might be
deliberated as nontoxic medicinal scaffolds to render normal calcification of bones and teeth.
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Microwave‐assisted synthesis of 1‐substituted‐1H‐benzimidazolium salts: Non‐competitive inhibition of human carbonic anhydrase I and II
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1‐Substituted‐1H‐benzimidazolium p‐toluenesulfonate salts were generated by microwave‐assisted synthesis and their two iodide salts were synthesized by anion exchange reaction. The crystal structure
of 1‐methoxyethyl‐1H‐benzimidazolium p‐toluenesulfonate showed that cation and anion are interconnected by N‐H···O and C‐H···O hydrogen bonds. The iodide salts showed stronger inhibitory activity on
hCA I/II than the corresponding p‐toluenesulfonate salts. Abstract A series of 1‐substituted‐1H‐benzimidazolium p‐toluenesulfonate salts were synthesized in good yields by the reaction of
1‐substituted benzimidazole derivatives and p‐toluenesulfonic acid under microwave irradiation. Two iodide salts were synthesized by the anion exchange reaction of the corresponding
p‐toluenesulfonate salt and NaI. All compounds were characterized by 1H NMR, 13C NMR, IR, LC‐MS spectroscopic methods, and elemental analyses. The crystal structure of
1‐methoxyethyl‐1H‐benzimidazolium p‐toluenesulfonate 2d showed that cation and anion are interconnected by N−H···O and C−H···O hydrogen bonds. All compounds were examined as inhibitor of human
carbonic anhydrase (hCA) I and II, and all of them inhibited hCA I and hCA II. Kinetic investigation results revealed that these compounds inhibit hCA I and hCA II in a non‐competitive manner. The
iodide salts had higher inhibitory activity than their corresponding p‐toluenesulfonate salts.
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Liposomes actively recognizing the glucose transporter GLUT1 and integrin αvβ3 for dual‐targeting of glioma
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In order to develop an efficient glioma‐targeting drug delivery system, a glioma‐targeted glucose‐RGD (Glu‐RGD) derivative was designed and synthesized as ligand for preparing liposomes to
effectively deliver paclitaxel (PTX) to cross the blood–brain barrier. The uptake and concentration efficiencies were enhanced compared to naked PTX. Glu‐RGD‐Lip may be used as a delivery system for
PTX to treat integrin αvβ3‐overexpressing tumor‐bearing mice. Abstract The treatment of glioma is a great challenge because of the existence of the blood–brain barrier (BBB). In order to develop an
efficient glioma‐targeting drug delivery system to greatly improve the brain permeability of anti‐cancer drugs and target glioma, a novel glioma‐targeted glucose‐RGD (Glu‐RGD) derivative was designed
and synthesized as ligand for preparing liposomes to effectively deliver paclitaxel (PTX) to cross the BBB and target glioma. The liposomes were prepared and characterized for particle size, zeta
potential, encapsulation efficiency, release profile, stability, hemolysis, and cell cytotoxicity. Also, the Glu‐RGD modified liposomes showed superior targeting ability in in vitro and in vivo
evaluation as compared to naked PTX, non‐coated, singly modified liposomes and liposomes co‐modified by physical blending. The relative uptake efficiency and concentration efficiency were enhanced by
4.41‐ and 4.72‐fold compared to that of naked PTX, respectively. What is more, the Glu‐RGD modified liposomes also displayed the maximum accumulation of DiD‐loaded liposomes at tumor sites compared
to the other groups in in vivo imaging. All the results in vitro and in vivo suggested that Glu‐RGD‐Lip would be a potential delivery system for PTX to treat integrin αvβ3‐overexpressing
tumor‐bearing mice.
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Chemical structure modifications and nano‐technology applications for improving ADME‐Tox properties, a review
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The chemical structure of a drug molecule affects its physicochemical properties and subsequent biological activities. This review discusses chemical and pharmaceutical approaches for circumventing
structure‐related problems and achieving acceptable ADME‐Tox properties. Attention is paid to modern therapeutic candidates and targets. Abstract The chemical structure of a drug molecule affects its
physicochemical properties and subsequent biological activities. Many pharmacologically active molecules fail to reach the market or have an inconvenient route of administration due to their chemical
structure. This is especially important with the recent tendency to develop drug candidates beyond the drug‐likeness space for addressing difficult targets such as protein–protein interfaces. The
objective of this review is to discuss chemical and pharmaceutical approaches for circumventing structure‐related problems and achieving acceptable ADME‐Tox properties. The chemical
structure‐associated limitations are critically discussed. Chemical modifications and pharmaceutical technology applications for improving drug‐likeness are illustrated. Attention is paid to modern
therapeutic candidates and targets. In conclusion, chemical modifications as well as nanotechnology applications can be used effectively to enhance absorption, permeability, and selective
distribution to a body compartment, to improve drug specificity, to limit off‐target toxicity as well as to enhance stability and to protect against metabolism. The nano‐technology‐based solutions
are relatively easier to develop over a new molecular entity, but adopting the chemical approach is more established in terms of safety, quality control, and regulatory assessment methods.
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Fe3O4 nanoparticles mediated synthesis of novel spirooxindole‐dihydropyrimidinone molecules as Hsp90 inhibitors
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Novel spirooxindole‐dihydropyrimidinones were synthesized by Fe3O4 nanoparticles intervened synthesis and their Hsp90 ATPase inhibitory activities were investigated. All compounds showed a moderate
to potent ATPase inhibitory profile, with IC50 values ranging from 0.18 to 6.80 µM, Compounds 4j, 4h, 4f, and 4i were more active than the standard, geldanamycin. Abstract Heat shock protein 90
(Hsp90) is a validated molecular chaperone considered as the new key recipient for cancer intervention. The current study illustrates the synthesis of novel spirooxindole‐dihydropyrimidinones (4a–j)
by Fe3O4 nanoparticles intervened synthesis and their Hsp90 ATPase inhibitory activity was investigated by the malachite green assay. All the compounds in the study demonstrated a moderate to potent
ATPase inhibitory profile, with IC50 values ranging from 0.18 to 6.80 μM. Compounds 4j, 4h, 4f, and 4i exhibited maximum inhibitory potential with IC50 values of 0.18, 0.20, 0.35, and 0.55 μM,
respectively. They were found to be better than the standard drug, geldanamycin (Hsp9 ATPase inhibition IC50 = 0.90 μM). Compounds 4h and 4j with IC50 values of 22.82 ± 0.532, 20.78 ± 0.234 and
21.32 ± 0.765, 28.43 ± 0.653 µM showed significantly greater potencies against the MCF‐7 and HepG2 cell lines, respectively. Compound 4j showed good antioxidant activities in the DPPH test and H2O2
assay (IC50 = 20.13.23 ± 0.32 and 23.27 ± 0.32 μg/mL) when compared with the standard ascorbic acid (IC50 = 19.16 ± 0.20 and 20.66 ± 1.09 μg/mL). A molecular docking study was performed to observe
the binding efficiency and steric interactions of the lead moiety.
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Anti‐proliferative and anti‐malarial activities of spiroisoxazoline analogues of artemisinin
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A series of spiroisoxazoline analogues of artemisinin was synthesized and evaluated for their anti‐proliferative and anti‐malarial activities. Compound 11a demonstrated anti‐proliferative activities
against the human cancer cell line HCT‐15 and compound 11b showed excellent anti‐plasmodial activity. Molecular docking studies of 11b suggest that this class of compounds binds differently to
cysteine proteases compared to the C‐10 modified analogs. Abstract A series of spiroisoxazoline analogues of artemisinin was synthesized by employing 1,3‐dipolar cycloaddition between various in situ
generated nitrile oxides and artemisitene. All the synthesized compounds were tested for their anti‐proliferative and anti‐malarial activities. Among the compounds tested, compound 11a was found to
be potent against the HCT‐15 cancer cell line with IC50 = 4.04 μM when compared to 5‐fluorouracil (IC50 = 35.53 μM). DNA cell cycle analysis shows that 11a was inhibiting cell proliferation at the
G2/M phase. Compound 11b was found to be most active against Plasmodium falciparum with IC50 = 0.1 μM and also blocked host hemoglobin hydrolysis by the falcipain‐3 receptor. It was demonstrated to
have better dynamics of parasite killing efficiency than artemisinin. Molecular docking studies revealed that these compounds interacted with falcipain‐3 receptor sites.
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Semi‐synthesis, antibacterial activity, and molecular docking study of novel pleuromutilin derivatives bearing cinnamic acids moieties
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Pleuromutilin–cinnamic acids hybrids were synthesized via molecular assembly and evaluated for their in vitro antibacterial activity and their in vivo efficacy in mice lethally infected with
methicillin‐resistant Staphylococcus aureus (MRSA). Among those compounds assayed, 13u offered good results both in vitro and in vivo. Abstract To develop new antibiotics owning a special mechanism,
we used the molecular assembly method to synthesize a series of novel pleuromutilin derivatives containing a cinnamic acid scaffold at the C‐14 side chain. We evaluated their antibacterial activity
and used in silico molecular docking to study their binding mode with the target. The structure–activity relationship (SAR) study suggested that compounds with NO2 (13e), OH (13u), and NH2 (13y)
appeared more active (0.0625–2 µg/mL) in vitro against several penicillin‐resistant Gram‐positive bacteria and the position of the substituent on the benzene ring would affect the activity. The in
vivo efficacy investigation of 13e, 13u, and 13y with once daily intragastric (i.g.) administration at 40 mg/kg for 3 consecutive days in a mouse systemic infection model showed that 13u had equal
activity as valnemulin providing the mice with 60% survival, while 13e and 13y gave 30 and 40% survival, respectively. The molecular docking studies indicated that π–π stacking and hydrogen bond
formation played important roles in improving the antibacterial activity.
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Synthesis and in vitro anti‐platelet aggregation activities of 2‐methoxy‐5‐arylamido‐N‐(pyridin‐3‐yl‐methyl)benzamides
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In an effort to find novel antiplatelet drugs, structural modifications of picotamide were made to synthesize a series of 2‐methoxy‐5‐arylamido‐N‐(pyridin‐3‐ylmethyl)benzamides and evaluate their in
vitro anti‐platelet aggregation activity and in vitro cell toxicity. With their higher anti‐platelet aggregation activities and cell toxicities, compounds 1b–d and 1l,m have potential as a novel kind
of anti‐platelet drugs. Abstract In order to discover novel compounds with anti‐platelet aggregation activities, a series of novel 2‐methoxy‐5‐arylamido‐N‐(pyridin‐3‐ylmethyl)benzamides (1a–n) were
synthesized and their anti‐platelet aggregation activities were evaluated by the turbidimetric method in response to the following agonists: adenosine diphosphate (ADP) (5 mM/L), arachidonic acid
(AA) (20 µM/L), and collagen (1 mg/mL). Those synthesized compounds that have better in vitro activities were subjected to cell toxicity tests via cell counting kit‐8 (CCK‐8) assay. The biological
evaluation revealed that compound 1a (IC50: 0.21 µM/L) exhibited the highest anti‐platelet aggregation activities when ADP was selected as an inducer, and compound 1b (IC50: 0.23 µM/L) showed the
best activities when AA was selected as inducer, and compound 1m (inhibition rate: 55.06%) had significant anti‐platelet aggregation activities when collagen was selected as inducer among all target
compounds. Moreover, the effect of cell toxicity exhibited that none of the compounds had obvious cell toxicity against L929 cells. Therefore, 2‐methoxy‐5‐arylamido‐N‐(pyridin‐3‐ylmethyl)benzamides
have the potential to become a novel kind of anti‐platelet drugs and deserve further study.
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Therapeutic advancement of benzothiazole derivatives in the last decennial period
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This review mainly focuses on the research work on different pharmacological activities of benzothiazole‐based compounds carried out in the last decennial period. A list of patents is also included.
Abstract Benzothiazole, a fused heterocyclic moiety, has attracted synthetic and medicinal chemists for good reasons. It is a valuable scaffold that possesses diverse biological activities, such as
anticancer, anti‐inflammatory, antimicrobial, antiviral, antimalarial, and anticonvulsant effects. This review mainly focusses on the recent research work on the different biological activities of
benzothiazole‐based compounds.
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Interconnection of sulfides and sulfoxides in medicinal chemistry
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Aromatic heterocycles with basic nitrogen atoms and carboxylic acid derivatives dominate the chemical space of drug‐like molecules. These established structural motifs have to be combined with
elements of diversity in order to be able to tackle seemingly undruggable targets. Examples for functionalities related to improved solubility, reduced drug resistance, linkers in drug conjugates,
and drug‐targeting to parasites are discussed. Abstract Aromatic heterocycles with basic nitrogen atoms as well as carboxylic acid derivatives are the dominating chemical space in the universe of
drug‐like molecules. These established and exceedingly evaluated structural motifs have to be combined with elements of diversity in order to chart less well‐explored galaxies of chemical space and
to be able to tackle seemingly undruggable targets. Flat scaffolds should be replaced by shapely molecular cores. In this context, it has been unheeded that phenyl rings in diaryl sulfides are less
co‐planar than in ethers and that the metabolic interconnection of sulfides and sulfoxides offers advantages that are unalike from the chemistry of amines and N‐oxides in the CHN‐O world. Moreover,
σ‐hole potentials increase with the polarizability of the atom N < P < O < S and do not only play a role in long‐time overlooked halogen bonds. Examples for λ2, λ4, and λ6 S‐based
functionalities related to improved solubility, reduced drug resistance, linkers in drug conjugates, drug‐targeting to parasites, and as basis for drug monitoring in sports are given and discussed.
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Isolation, synthesis, and cytotoxicity evaluation of two impurities in nomegestrol acetate
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Nomegestrol acetate (NOMAc), a synthetic progesterone analog, can be synthesized by several routes with similar impurity profiles. Two impurities, A and B, were confirmed by synthesis and evaluated
for their in vitro cytotoxicities against diverse cell lines. While NOMAc and impurity A showed cytotoxicity to L02, MCF‐7, and C33A cells at high concentrations, impurity B was not cytotoxic to any
of the cell lines tested. Abstract Nomegestrol acetate (NOMAc) is a synthetic progesterone analog and classified as a fourth‐generation progestin. It has been approved in many countries for oral
contraception, hormonal replacement therapy (HRT), and treatment of various gynecological disorders. There are several synthetic routes reported for the synthesis of NOMAc and they all share the very
similar last three to five steps toward the conversion of 6‐methylene to 6‐methyl‐6,7‐unsaturated structure. Therefore the final product from different processing routes may have similar impurity
profiles. In the analysis of NOMAc, we identified two impurities, impurity A (listed in EP 8.0) and impurity B (not specified in EP 8.0). Both impurities were further confirmed by synthesis. In
addition, both impurities and NOMAc were evaluated for their in vitro cytotoxicities against L02 liver cells, mesenchymal stem cells, MCF‐7 breast cancer cells, and C33A cervical cancer cells. These
three analogs are not cytotoxic to the four cell lines at low concentrations (<20 μM). NOMAc and impurity A showed cytotoxicity to L02, MCF‐7, and C33A cells at high concentrations, while impurity
B did not show significant cytotoxicity to any of the cell lines tested.
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Synthesis, crystal structure, and biological evaluation of optically active 2‐amino‐4‐aryl‐7,7‐dimethyl‐5‐oxo‐5,6,7,8‐tetrahydro‐4H‐chromen‐3‐carbonitriles: Antiepileptic, antidiabetic, and anticholinergics potentials
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In the presence of chiral organic catalysts, the optically active 4H‐chromine was synthesized from multicomponent condensation of 5,5‐dimethylcyclohexane‐1,3‐dione with malononitrile and
methylene‐active compound. The resulting eugenol bearing oxypropanolamine derivatives were effective inhibitors of α‐glycosidase, cytosolic carbonic anhydrases I and II, and acetylcholinesterase.
Abstract In the presence of chiral organic catalysts, the optically active 4H‐chromine was synthesized from the multicomponent condensation of 5,5‐dimethylcyclohexane‐1,3‐dione with malononitrile and
methylene‐active compound, and the specific angle of rotation of the compounds was determined in the AUTOPOL‐III polarimeter and their structures were confirmed by the X‐ray spectroscopic analysis
method. These optically active 2‐amino‐4‐aryl‐7,7‐dimethyl‐5‐oxo‐5,6,7,8‐tetrahydro‐4H‐chromen‐3‐carbonitriles were effective inhibitors of α‐glycosidase, the cytosolic carbonic anhydrase I and II
isoforms (hCA I and II), and acetylcholinesterase (AChE) enzymes with Ki values in the range of 21.33 ± 1.11 to 40.24 ± 10.78 μM for hCA I, 28.91 ± 6.51 to 59.97 ± 15.62 μM for hCA II, 18.16 ± 3.18
to 66.57 ± 1.36 μM for α‐glycosidase, and 8.68 ± 0.93 to 102.61 ± 24.96 μM for AChE.
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Aminopyrazole‐substituted metallophthalocyanines: Preparation, aggregation behavior, and investigation of metabolic enzymes inhibition properties
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4‐(2‐(5‐Amino‐4‐(4‐bromophenyl)‐3‐methyl‐1H‐pyrazol‐1‐yl)ethoxy)phthalonitrile 2 and its soluble aminopyrazole‐substituted peripheral metallophthalocyanine complexes 3–5 were synthesized and assayed
for their aggregation behavior, antimicrobial, antidiabetic, and anticholinergic properties. They were found to be effective inhibitors of α‐glycosidase, acetylcholinesterase, human carbonic
anhydrase I and II, and butyrylcholinesterase. Abstract The synthesis, characterization, aggregation behavior, theoretical studies, and investigation of antimicrobial, antidiabetic, and
anticholinergic properties of 4‐(2‐(5‐amino‐4‐(4‐bromophenyl)‐3‐methyl‐1H‐pyrazol‐1‐yl)ethoxy)phthalonitrile (2) and its soluble aminopyrazole‐substituted peripheral metallo (Mn, Co, and
Ni)‐phthalocyanine complexes (3–5) are reported for the first time. The synthesized compounds and phthalocyanine complexes were characterized spectroscopically. The new phthalonitrile derivative (2)
and its peripheral metallophthalocyanine complexes (3–5) were found to be effective inhibitors of α‐glycosidase, acetylcholinesterase (AChE), human carbonic anhydrase I and II isoforms (hCA I and
II), and butyrylcholinesterase (BChE) with Ki values in the range of 1.55 ± 0.47 to 10.85 ± 3.43 nM for α‐glycosidase, 8.44 ± 0.32 to 21.31 ± 7.91 nM for hCA I, 11.73 ± 2.82 to 31.03 ± 4.81 nM for
hCA II, 101.62 ± 26.58 to 326.54 ± 89.67 nM for AChE, and 68.68 ± 11.15 to 109.53 ± 19.55 nM for BChE. This is the first study of peripherally substituted phthalocyanines containing an aminopyrazole
group as potential carbonic anhydrase enzyme inhibitor. Also, the antimicrobial activities of the synthesized compounds were evaluated against six microorganisms (four bacteria and two Candida
species) using the broth microdilution method. The gram‐positive bacteria were detected to be more sensitive than gram‐negative bacteria and yeasts in the synthesized compounds.
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Efficient synthesis of meso‐substituted porphyrins and molecular docking as potential new antioxidant and cytotoxicity agents
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Novel mesotetrakis[aryl]‐21H,23H‐porphyrin derivatives 2a–h were synthesized through an improved methodology, characterized and evaluated as antioxidant and cytotoxic agents. Molecular docking was
performed to investigate the binding between the active porphyrins and the molecular targets Bcl‐2 and caspase‐3. Abstract An improved methodology is reported for the synthesis of new series of
mesotetrakis[aryl]‐21H,23H‐porphyrin derivatives 2a–h and was considered as a model to study their antioxidant and cytotoxic activities. The structures of the novel compounds were determined in 1H
and 13C NMR, UV‐Vis, and elemental analyses. Among the derivatives, compounds 2c, 2d, and 2h showed strongest radical‐scavenging activity. Moreover, according to our results, compounds 2c, 2d, 2g,
and 2h have very strong activity against the HepG2 hepatoma cell line, with IC50 values from 9 to 25 μg/mL. Molecular docking was performed to investigate the binding between the most active
porphyrin derivatives 2c, 2d, 2g, 2h and the two molecular targets Bcl‐2 and caspase‐3. Compounds 2c and 2d seem to have better affinities to both proteins than 2g and 2h.
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Novel acyl thiourea derivatives: Synthesis, antifungal activity, gene toxicity, drug‐like and molecular docking screening
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In an in vitro antifungal screening of nine novel acyl thioureas, three (3, 5, and 6) show high activity against 11 fungi and 3 oomycete strains of phytopathogenic significance. Analysis of gene
toxicity, drug likeness, and calculations of frontier molecular orbitals demonstrate their low toxicity profile. Molecular docking studies point to 14α‐demethylase and N‐myristoyltransferase as
possible antifungal targets. Abstract Nine novel acyl thioureas were synthesized. Their identities and purities were confirmed by LC‐MS spectra; each structure was elucidated by elemental analysis,
IR, 1Н and 13C NMR spectra. Applying an in vitro screening of their antifungal potential, three substances (3, 5, and 6) could be selected as showing high activity against 11 fungi and 3 Phytophthora
strains of phytopathogenic significance. Analysis of gene toxicity with the Salmonella reverse mutagenicity test, as an assessment of drug likeness, lipophilicity, and calculations of frontier
molecular orbitals assign a low toxicity profile to these compounds. Molecular docking studies point to 14α‐demethylase (CYP51) and N‐myristoyltransferase (NMT) as possible fungal targets for growth
inhibition. The findings are discussed with respect to structure–activity relationship (SAR).
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Design, synthesis, and biological evaluation of new pyrazino[1,2‐a]benzimidazole derivatives as selective cyclooxygenase (COX‐2) inhibitors
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A new series of pyrazino[1,2‐a]benzimidazoles were synthesized to evaluate their biological activities as selective cyclooxygenase‐2 (COX‐2) inhibitors, anti‐cancer and anti‐platelet aggregation
agents. Compound 5g was recognized as the most potent COX‐2 inhibitor (IC50 = 0.08 µM) and 5m displayed the highest selectivity index (SI > 909). Abstract A new class of
pyrazino[1,2‐a]benzimidazole derivatives possessing the SO2Me pharmacophore at the para position of the C‐3 phenyl ring was designed, synthesized, and tested for their cyclooxygenase‐2 (COX‐2)
inhibitory, anti‐cancer and anti‐platelet aggregation activities. In vitro COX‐1/COX‐2 inhibition studies showed that
2‐(4‐methylphenyl)‐1‐methylene‐3‐(4‐(methylsulfonyl)phenyl)‐1,2‐dihydropyrazino‐[1,2‐a]benzimidazole (5g) was the most potent COX‐2 inhibitor (IC50 = 0.08 μM) and
2‐(3,4,5‐trimethoxyphenyl)‐1‐methylene‐3‐(4‐(methylsulfonyl)phenyl)‐1,2‐dihydropyrazino‐[1,2‐a]benzimidazole (5m) had the highest selectivity index (SI > 909). Cytotoxicity of the synthesized
compounds was also determined against the MCF‐7 cell line. Most compounds were cytotoxic against MCF‐7 cells and our results showed that compound 5m exhibited the highest anti‐proliferative activity
compared to the reference compound, cisplatin. Our data also indicated that compound 5k was the most potent platelet aggregation inhibitor according to aggregometry test results.
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Synthesis of novel derivatives of 7,8‐dihydro‐6H‐imidazo[2,1‐b][1,3]benzothiazol‐5‐one and their virus‐inhibiting activity against influenza A virus
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A series of novel 2‐substituted 7,8‐dihydro‐6H‐imidazo[2,1‐b][1,3]benzothiazol‐5‐ones 3a–k were synthesized and evaluated for their influenza A virus‐inhibiting activity. Three analogues (3i–k)
containing a thiophene unit were found to exhibit high virus‐inhibiting activity and a favorable toxicity profile. Compound 3j (CC50: >1000 µM, SI = 77) is the best anti‐influenza hit analogue for
further structural optimization and drug development. Abstract Influenza remains a highly pathogenic and hardly controlled human infection. The ability of selecting drug‐resistant variants
necessitates the search and development of novel anti‐influenza drugs. Herein, we describe the synthesis and evaluation of a series of novel 2‐substituted
7,8‐dihydro‐6H‐imidazo[2,1‐b][1,3]benzothiazol‐5‐ones 3a–k for their virus‐inhibiting activity against influenza A virus. The new analogues 3a–k prepared in two steps from commercially available
cyclohexane‐1,3‐diones were fully characterized by their NMR and mass spectral data. Among the new derivatives screened for cytotoxicity and in vitro antiviral activity against influenza virus
A/Puerto Rico/8/34 (H1N1) in MDCK cells, three analogues 3i–k containing a thiophene unit were found to exhibit high virus‐inhibiting activity (high SI values) and a favorable toxicity profile. The
compound 3j (CC50: >1000 μM, SI = 77) with higher potency is the best anti‐influenza hit analogue for further structural optimization and drug development. The most active compounds did not
inhibit viral neuraminidase and possess therefore other targets and mechanisms of activity than the currently used neuraminidase inhibitors.
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